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A Pharmacokinetic and Pharmacodynamic Study of PF-04950615 (RN316) in Subjects With Hypercholesterolemia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01435382
Recruitment Status : Completed
First Posted : September 16, 2011
Results First Posted : July 23, 2018
Last Update Posted : July 23, 2018
Sponsor:
Information provided by (Responsible Party):
Pfizer

Brief Summary:
This Phase 1 study has been designed to evaluate the absolute bioavailability of PF-04950615 (RN316) in subjects with hypercholesterolemia who are not currently on lipid-lowering therapy.

Condition or disease Intervention/treatment Phase
Hypercholesterolemia Dyslipidemias Hyperlipidemias Lipid Metabolism Disorders Metabolic Diseases Biological: PF-04950615 (RN316) Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 49 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: A Phase 1, Open-label, Randomized, Single Dose, Parallel Group Study To Assess The Pharmacokinetics And Pharmacodynamics Of Pf-04950615 Following Subcutaneous And Intravenous Doses In Adult Subjects With Hypercholesterolemia
Actual Study Start Date : October 2011
Actual Primary Completion Date : February 2012
Actual Study Completion Date : April 2012

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Group A Biological: PF-04950615 (RN316)
Dose A - single-dose intravenous infusion

Experimental: Group B Biological: PF-04950615 (RN316)
Dose B - single-dose subcutaneous injection

Experimental: Group C Biological: PF-04950615 (RN316)
Dose C - single-dose subcutaneous injection

Experimental: Group D Biological: PF-04950615 (RN316)
Dose D - single-dose subcutaneous injection




Primary Outcome Measures :
  1. Maximum Observed Plasma Concentration (Cmax) of PF-04950615 [ Time Frame: Pre-dose, 30 minutes, 1, 8, 24, 48, 72, 96, 120, 168, 336, 504, 672, 840, 1008, 1176, 1344, 1512, 1680, 2016 hours post-dose ]
  2. Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-04950615 [ Time Frame: Pre-dose, 30 minutes, 1, 8, 24, 48, 72, 96, 120, 168, 336, 504, 672, 840, 1008, 1176, 1344, 1512, 1680, 2016 hours post-dose ]
  3. Area Under the Plasma Concentration-Time Curve From Time Zero to Time of Last Quantifiable Concentration (AUClast) of PF-04950615 [ Time Frame: Pre-dose, 30 minutes, 1, 8, 24, 48, 72, 96, 120, 168, 336, 504, 672, 840, 1008, 1176, 1344, 1512, 1680, 2016 hours post-dose ]
  4. Area Under the Plasma Concentration-Time Curve From Time Zero To Infinity (AUCinf) of PF-04950615 [ Time Frame: Pre-dose, 30 minutes, 1, 8, 24, 48, 72, 96, 120, 168, 336, 504, 672, 840, 1008, 1176, 1344, 1512, 1680, 2016 hours post-dose ]
  5. Apparent Clearance (CL/F) of PF-04950615 Subcutaneous Groups [ Time Frame: Pre-dose, 30 minutes, 1, 8, 24, 48, 72, 96, 120, 168, 336, 504, 672, 840, 1008, 1176, 1344, 1512, 1680, 2016 hours post-dose ]
    Clearance (CL) of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Apparent clearance (CL/F) is influenced by the fraction of the dose absorbed from plasma after SC administration of drug.

  6. Clearance (CL) of PF-04950615 Intravenous Group [ Time Frame: Pre-dose, 30 minutes, 1, 8, 24, 48, 72, 96, 120, 168, 336, 504, 672, 840, 1008, 1176, 1344, 1512, 1680, 2016 hours post-dose ]
    Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.

  7. Apparent Volume of Distribution (Vz/F) of PF-04950615 Subcutaneous Groups [ Time Frame: Pre-dose, 30 minutes, 1, 8, 24, 48, 72, 96, 120, 168, 336, 504, 672, 840, 1008, 1176, 1344, 1512, 1680, 2016 hours post-dose ]
    Volume of distribution (Vz) is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vz/F is influenced by the fraction of the dose absorbed from plasma after SC administration of drug.

  8. Volume of Distribution at Steady State (Vss) of PF-04950615 Intravenous Group [ Time Frame: Pre-dose, 30 minutes, 1, 8, 24, 48, 72, 96, 120, 168, 336, 504, 672, 840, 1008, 1176, 1344, 1512, 1680, 2016 hours post-dose ]
    Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vss is determined when overall intake of drug is in dynamic equilibrium with its elimination.

  9. Terminal Elimination Half-life (t1/2) of PF-04950615 [ Time Frame: Pre-dose, 30 minutes, 1, 8, 24, 48, 72, 96, 120, 168, 336, 504, 672, 840, 1008, 1176, 1344, 1512, 1680, 2016 hours post-dose ]
    t1/2 is the time measured for the plasma concentration of drug to decrease by one half.

  10. Absolute Bioavailability of PF-04950615 Subcutaneous Groups [ Time Frame: Pre-dose, 30 minutes, 1, 8, 24, 48, 72, 96, 120, 168, 336, 504, 672, 840, 1008, 1176, 1344, 1512, 1680, 2016 hours post-dose ]
    Bioavailability is defined as the rate and extent to which the active moiety administered drug reaches the systemic circulation. Absolute bioavailability of the subcutaneous doses was estimated by comparing log-transformed dose-normalized AUClast for subcutaneous to intravenous dose.


Secondary Outcome Measures :
  1. Absolute Value of Fasting Low-density Lipoprotein Cholesterol (LDL-C) [ Time Frame: Day 2, 3, 4, 5, 6, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 85 ]
  2. Percent Change From Baseline in Fasting Low-density Lipoprotein Cholesterol (LDL-C) at Day 2, 3, 4, 5, 6, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71 and 85 [ Time Frame: Baseline, Day 2, 3, 4, 5, 6, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 85 ]
    Baseline was the average of observations collected on Days 7 and 1 prior to the study treatment administration.

  3. Duration of Fasting LDL-C Suppressed Below 70 mg/dL and 100 mg/dL [ Time Frame: Day 1 up to Day 85 ]

Other Outcome Measures:
  1. Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Day 1 up to Day 85 ]
    An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. A treatment emergent AE was defined as an event that emerged during the treatment period that was absent before treatment, or worsened during the treatment period relative to the pretreatment state.

  2. Number of Adverse Events (AEs) by Severity [ Time Frame: Day 1 up to Day 85 ]
    An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An AE was assessed according to severity; mild (not causing any significant problem, dose adjustment not required), moderate (caused problem that does not interfere significantly with usual activities or the clinical status, dose adjustment needed due to adverse event) and severe (caused problem that interferes significantly with usual activities or the clinical status, study drug stopped due to adverse event).

  3. Number of Participants With Treatment Related Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Day 1 up to Day 85 ]
    An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.

  4. Number of Participants With Injection Site Reactions [ Time Frame: Day 1 up to Day 3 ]
    The injection site reaction included erythema, induration, ecchymosis, injection site pain, injection site pruritus.

  5. Number of Injection Site Reactions Reported as Adverse Events [ Time Frame: Day 1 up to Day 3 ]
    The injection site reactions included erythema, induration, ecchymosis, injection site pain and injection site pruritus. An adverse event was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship.

  6. Visual Analogue Scale (VAS) [ Time Frame: Day 1: Immediately post-dose, 0.5, 1.0, 2.0, 8.0 hours post-dose; Day 2, 3 ]
    Participants indicated the amount of pain experienced due to study drug injection, on a VAS of 0 (no pain) to 100 (very severe pain), where higher scores indicate higher intensity of pain.

  7. Number of Participants With Clinically Significant Laboratory Abnormalities [ Time Frame: Day 1 up to Day 85 ]
    Laboratory parameters evaluated for abnormalities were: hematology (hemoglobin [Hgb], hematocrit, red blood cell [RBC] count, platelets, white blood cell count [WBC], lymphocytes, total neutrophils, basophils, eosinophils, monocytes); coagulation (partial thromboplastin time, prothrombin time [PT], PT international ratio); clinical chemistry (glucose, creatine kinase, amylase, lipase); liver function (total, direct and indirect bilirubin, aspartate aminotransferase [AT], alanine AT, gamma-glutamyl transferase, alkaline phosphatase, total protein, albumin, lactate dehydrogenase); renal function (blood urea nitrogen, creatinine, uric acid); urinalysis (urine- specific gravity, pH, glucose, ketones, blood/Hgb, nitrite, leukocyte, esterase, RBC, WBC, epithelial cells, hyaline cast and bacteria); lipid (cholesterol); electrolytes (sodium, potassium, chloride, calcium, magnesium, phosphate, bicarbonate). Clinical significance of laboratory abnormalities were judged by investigator.

  8. Number of Participants With Clinically Significant Changes in Vital Signs [ Time Frame: Day 1 up to Day 85 ]
    Vital signs abnormalities included: maximum increase or decrease from baseline in supine systolic blood pressure (BP) greater than or equal to (>=) 30 millimeter of mercury (mmHg); maximum increase or decrease from baseline in supine diastolic BP of >=20 mmHg; supine pulse rate less than (<) 40 beats per minute (bpm) and greater than (>) 120 bpm; standing pulse rate less than (<) 40 beats per minute (bpm) and greater than (>) 140 bpm. Clinical significance of vital signs were judged by investigator.

  9. Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) [ Time Frame: Day 1 up to Day 85 ]
    ECG abnormalities included 1) PR interval: maximum >=300 maximum millisecond (msec), increase of >=25 percent (%) for baseline value of >200 msec and maximum increase of >=50% for baseline value of less than or equal to (<=) 200 msec; 2) QRS interval: maximum >=200 msec, maximum increase of >=25 % for baseline value of >100 msec and maximum increase of >=50% for baseline value of <=100 msec; 3) QT interval corrected using the Fridericia's formula (QTCF): 450 msec to <= 480 msec, 480 msec to <=500 msec, > 500 msec, maximum increase from baseline of >30 to <=60 msec and maximum increase from baseline of >60 msec. Clinical significance of ECG were judged by investigator.

  10. Percentage of Participants With Positive Anti-drug (Anti-PF 04950615) Antibodies [ Time Frame: Day 1 up to Day 85 ]
    Human serum samples of participants who received PF-04950615 were analyzed for the presence of anti-PF-04950615 antibodies by using the semi quantitative enzyme-linked immunosorbent assay (ELISA).



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Fasting LDL-C greater than or equal to 130 mg/dL at two qualifying screening visits.
  • Total body weight greater than or equal to 50 kg (110 lbs) and less than or equal to 150 kg (330 lbs)

Exclusion Criteria:

  • Lipid-lowering prescription medications, homeopaths, herbal medicines, or nutritional supplements.
  • Poorly controlled type 1 or type 2 diabetes.
  • History of a cardiovascular or cerebrovascular event or related procedure during the past year.
  • Poorly controlled hypertension.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01435382


Locations
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United States, California
Profil Institute for Clinical Research, Inc.
Chula Vista, California, United States, 91911
United States, Florida
Elite Research Institute
Miami, Florida, United States, 33169
United States, Kansas
Vince and Associates Clinical Research
Overland Park, Kansas, United States, 66212
United States, Maryland
PAREXEL International - Baltimore Early Phase Clinical Unit
Baltimore, Maryland, United States, 21225
United States, Michigan
Jasper Clinic, Inc.
Kalamazoo, Michigan, United States, 49007
United States, Minnesota
Prism Research
Saint Paul, Minnesota, United States, 55114
United States, Ohio
Medpace Clinical Pharmacology Unit
Cincinnati, Ohio, United States, 45212
Sponsors and Collaborators
Pfizer
Investigators
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Study Director: Pfizer CT.gov Call Center Pfizer
Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT01435382    
Other Study ID Numbers: B1481006
First Posted: September 16, 2011    Key Record Dates
Results First Posted: July 23, 2018
Last Update Posted: July 23, 2018
Last Verified: October 2017
Keywords provided by Pfizer:
PF-04950615
RN316
Additional relevant MeSH terms:
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Hypercholesterolemia
Dyslipidemias
Hyperlipidemias
Metabolic Diseases
Lipid Metabolism Disorders
Bococizumab
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents